The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the α-ketoamide 13b . We show that with the inhibitors the free energy cost to reach the charge-separated state of the active-site dyad is lower, with N3 inducing the most significant reduction. We also show that a few key sites (including specific water molecules) significantly enhance or reduce the thermodynamic feasibility of the PT reaction, with selective desolvation of the active site playing a crucial role. The approach presented is a cost-effective procedure to identify the enzyme regions that control the activation of the catalytic reaction and is thus also useful to guide the design of inhibitors.
【초록키워드】 feasibility, inhibitors, SARS-CoV-2 main protease, Region, inhibitor, reduction, Activation, enzyme, complex, transfer, Cys145, His41, covalent binding, selective, water molecules, approach, ENhance, identify, significantly, required, activated, reduce, catalytic, thermodynamic, desolvation, 【제목키워드】 SARS-CoV-2, Thermodynamics, tuning, catalysis, proton,